Centella asiatica (CA) is an Ayurvedic herb reputed to be rejuventating to nerves. Our long term goal is to investigate the efficacy of CA in peripheral and central neuropathies. The specific aims of this project are to investigate the safety, tolerability, potential therapeutic efficacy and bioavailability of a commercial CA triterpene mixture (CAST) in patients with diabetic neuropathy. This patient group and product were selected because an identical product (TTFCA), a mixture of asiaticoside, asiatic acid and madecassic acid, improves microcirculation in patients with diabetic neuropathy and is well tolerated at up to 180mg daily for 12 months. Importantly, we have also shown that CA ethanol extract speeds nerve regeneration in vivo in a rat sciatic nerve crush model on oral administration. The extract, and its triterpene components asiaticoside asiatic acid and madecassic acid stimulate neurite elongation in SH-SY5Y neuroblastoma cells, an in vitro model with excellent correlation to the rat model. CAST can therefore potentially both stimulate nerve regeneration and improve microcirculation in diabetic neuropathy. We will evaluate CAST at the highest tolerated dose to avoid the pitfalls of insufficient dosing. The project is a double-blind, placebo-controlled study (n = 30 per group) beginning with a 12 week dose escalation phase (120 to 240mg CAST daily) with monthly evaluation of safety and tolerabilty. In the treatment phase (weeks 13-52), each patient will receive their individual highest tolerated dose with 3-monthly evaluation of safety and tolerability. Neurological assessments will be made at 0, 6 and 12 months. The primary outcome measure will be total neuropathic symptom score. Secondary outcomes will be neurological disability score, nerve conduction measurements and quantitative sensory testing. Statistical analyses will compare changes from baseline for CAST and placebo treated groups at both time points, compare effects of CAST at 6 and 12 months and, if numbers permit, compare doses. Asiatic and madecassic acids will be measured in plasma from the CAST group to identify therapeutic and/or unsafe levels. Stability of CAST will be monitored regularly throughout the study. Relevance: Diabetic neuropathy is a common complication of diabetes, affecting 30% of diabetics, reducing quality of life and often leading to foot ulceration and amputation. This project evaluates a product derived from the herb Centella asiatica, as a potential cure for this distressing, presently irreversible, condition. [unreadable] [unreadable] [unreadable]